A number of synthetic modifications of the vasopressin and oxytocin structures have been reported to give antagonistic activities. Such structures contain units which are derived from .beta.-mercapto-.beta.,.beta.-dialkylpropionic acid, for example, deamino-penicillanic acid or .beta.-mercaptopropionic acid, substituted for the cysteine unit at position 1 of the structure of the natural product: J. Lowbridge et al., J. Med. Chem. 22 565 (1979); M. Manning et al., J. Med. Chem. 20 1228 (1977); K. Bankowski et al., J. Med. Chem. 21 350 (1978); H. Schulz et al., J. Med. Chem. 9 647 (1966).
Ferring, A. B., European Pat. No. 112,809-A, discloses that certain oxytocin compounds with Mpr at position 1 have anti-OXT activity.
Later studies by M. Manning et al., J. Med. Chem. 25 (1982) and Peptides: Chemistry, Structure and Biology (Ann Arbor Sciences) 737 (1975), demonstrated that no clearly consistent pattern of increasing or decreasing antagonist potency has emerged but, in most of the series studied, the .beta.,.beta.-diethyl and .beta.,.beta.-cyclopentamethylene propionic acid units at position 1 were more active than were the lower homologues, see column 1 on page 411 of the first reference.
We have previously found that removing the proline unit from the tail units, at position 7, on 1-Pmp-VSP structures gave compounds which retained the VSP antagonist activity of the parent compounds, F. Ali et al., Ser. Nos. 586,933 and 586,934, both filed on Mar. 7, 1984 and now issued, U.S. Pat. Nos. 4,481,193 and 4,481,194, respectively. Now, we have found that removing the proline from a 1-dPen or Mpr-VSP derivative gives strong V.sub.1 -antagonism with a shift in the V.sub.1 :V.sub.2 ratio to the former.
In the description herein and in the claims, the nomenclature common in the art of peptide and, more specifically, vasopressin chemistry is used. When no configuration is noted, the amino acid unit is in the L, or naturally occuring, form. The thio members of the .beta.-mercaptopropionic acid (1) and cysteine (6) units are added for clarity in certain structural formulas.
Exemplary of the peptide art designations used herein are the following: dPen, .beta.-mercapto-.beta.-.beta.-dimethylpropionic acid; Mpr, .beta.-mercaptopropionic acid; Thr, threonine; Orn, ornithine; OXT, oxytocin; Abu, .alpha.-aminobutyric acid; Chg, cyclohexylglycine; Cha, cyclohexylalanine; Pba, .alpha.-aminophenylbutyric acid; Gln, glutamine; Gly, glycine; Tyr, tyrosine; Phe, phenylalanine; Val, valine; Ile, isoleucine; Nle, norleucine; Leu, leucine; Ala, alanine; Lys, lysine; Arg, arginine; Harg, homoarginine, Asn, asparagine; Tos, tosylate; BHA, benzhydrylamine; DIEA, diisopropylethylamine; 4-MeBzl, 4-methylbenzyl; TFA, trifluoroacetic acid; DCC, dicyclohexylcarbodiimide; HBT, 1-hydroxybenzotriazole; ACM, acetamidomethyl; Mpa, generic .beta.-mercaptopropionic acids.